A new experimental model has been found in this laboratory whereby Acute Hemorrhagic Pancreatitis with Fat Necrosis is induced in 100 percent of mice fed a choline-deficient diet supplemented with 0.5 percent dl-ethionine. The onset of the pancreatic necrosis has been shown to be due to activation of pancreatic zymogens leading to the intraparenchymal formation of significant amounts of free elastase, chymotrypsin and trypsin. Increasing levels of amylase, trypsin and/or chymotrypsin are detected also in the serum of the animals. The experimental model mimics very closely the clinical manifestations, the anatomopathologic findings and the purported pathogenesis of Acute Hemorrhagic Pancreatitis with Fat Necrosis seen in humans. Among experimental models of this disease, the present model seems to be unique inasmuch as the proteolytic enzymes responsible for the necrosis of the organ arise endogenously, as is the case in the human disease, rather than been introduced as such in the organ, as in the case with most other experimental models. Thus, even though it is most improbable that either ethionine or choline deficiency have any role in the etiology of the human disease, the new experimental model appears to be particularly suited for investigating what factors are capable of leading to the intraparenchymal activation of pancreatic zymogens which is responsible for the necrosis of the organ. Identification of these factors could shed some light and aid our understanding of the mechanisms operating in the human disease. Exploration of these factors is the main objective of the research proposed in this application. We shall pursue our studies by using, among other techniques, electron microscopy radioautography and in vitro methodologies to study alterations in the secretion of pancreatic enzymes; incorporation of labeled precursors to study the biosynthesis and turnover of zymogens and that of the membrane of acinar cells organelles, especially those of the endoplasmic reticulum; enzyme assay and electron microscopy histochemistry to assess the functional state of lysosomes; and pH probes to study changes in the internal pH of the zymogen granules.